Thursday, March 12, 2015

Always Remember, Never Forget: Fear Memory Retrieval and Conditioning

Let’s suppose that you are
strolling through a park on a Saturday afternoon. All goes well until a
mountain lion pounces out of the bushes and stares you right in the eye as it
salivates for some human flesh. What would you do?

Naturally,
when you encounter danger, it’s only natural to feel afraid. In this instance,
you are very afraid of the mountain lion standing 8 feet away from you, and in
response to this fear, your body induces a “fight or flight” response as it
prepares to defend itself against danger or avoid it. When this “fight or
flight” response takes effect, you decide to slowly inch for way toward the
grocery store just across the street, hoping that the cougar will remain calm.
Luckily, a park patrol comes around in his scooter and tranquilizes the animal
before it is able to react, and you are able to avoid the danger posed by the
presence of this mountain lion in the park.

"Fight or Flight" Response

http://www.simplypsychology.org/stress-biology.html

After this
encounter, you become slightly weary of walks in the park or you panic whenever
you hear the bushes rustling near you. You begin to have this new awareness
toward your surroundings while at the park because your body is able to develop
fear memories to avoid this danger and increase your chance of survival in the future.
In this case, your body develops a fear memory of mountain lions at the park,
and this fear memory can be retrieved throughout your lifetime. For some time,
you’ll most likely avoid spending your Saturday afternoons at the park, but
over time, your body will become conditioned to this fear and you would take
your walks as usual.

In this, we
see the relevance of fear memory development, retrieval, and conditioning as we
experience everyday life. Interestingly, fear memory can also play a significant
in anxiety disorders, including PTSD (post-traumatic stress disorder). PTSD is
characterized by changes or damage to the body’s “fight or fight” response that
causes an individual to feel stressed or frightened even when they are not in
danger. While scientists have a general understanding of neuroanatomy and the
effects of PTSD on mental health, the impaired mechanisms behind the disease
are still yet unknown.

Our understanding of neuroanatomy allows
us to identify particular brain structures that are involved in fear memory,
and ultimately PTSD. The amygdala, for example, is a brain structure known for
its role in emotion, learning, and memory, and appears to be active in fear
acquisition. It is also involved in learning not to fear, as it works in conjunction
with the prefrontal cortex, which is involved with decision-making,
problem-solving, and judgment.

To better understand the mechanisms
of fear memory retrieval and conditioning in the amygdala and PFC, Do-Monte et
al. looked specifically at fear memory retrieval circuits. They began by
administering a mild shock on rats to induce fear, and tested the rats for fear
memory retrieval circuits with respect to time. When the shock was
administered, a chemical response was projected from the pre-limbic prefrontal
cortex (PL) to the basolateral amygdala (BLA) and central nucleus of the
amygdala (CeA).

In order to
analyze temporal changes in fear memory retrieval circuits, they studied neural
activity using a marker, which determined the activation of each key structure
throughout the retrieval circuits. The marker, c-Fos, showed consistent
activation in the PL, suggesting that it is necessary for both early and late
memory retrieval. Conversely, after 24 hours there was a gradual shift in BLA activation
from the PL to the increased activation
of the paraventricular region of the thalamus (PVT) from the PL. Ultimately,
memory retrieval circuit shifts from a PL-BLA circuit to PL-PVT-CeA over time.
This indicates that the PVT is gradually recruited for fear retrieval in a
time-dependent manner, where this pathway may be necessary for fear memory retrieval
at late points in an animal’s lifetime.

Neural Pathways involved in early and late memory retrieval

The
investigation on the role of PVT activation continued in the work done by Penzo
and his colleagues. Specifically with respect to the PL-PVT-CeA retrieval
circuit, we see that the PVT is involved in fear processing and conditioning by
activating the CeA. This means that PVT is involved in allowing for you to
return to your routine of taking walks in the park, because your body
recognizes that the source of danger is no longer present at the park.

This process of activation can be
impaired, however, due to a deletion of a brain-derived neurotrophic factor
(BDNF), which binds to a TrkB receptor to activate the memory-storing CeA
neurons. The consequent of this deletion, in turn, induces constant fearful
responses as a result of the storage of fearful memories, which are not
conditioned.

“While our memories feel constant
across time, the neural pathways supporting them actually change with time,”
explains Do-Monte. The neural pathways supporting our memories allow for us to
develop, retrieve, and condition our fear memories, in order for us to survive.
With time, however, we see that dysregulation of retrieval circuits can result
in inappropriate fearful memory storage, which may contribute to exacerbated
fear responses in PTSD that occur long after a traumatic event occurs.

Do-Monte et al. and Penzo et al.
provide us with insight regarding the mechanisms of fear memory retrieval in
rats, which is applicable to humans. Their work has identified new pathways for
old memories, which shows that fearful events may occur months or years prior
to the onset of symptoms for patients with PTSD. This informs our understanding
of PTSD and ways in which neural pathways can be targeted for therapy.

2 comments:

This is interesting that you can find the faulty wiring of PTSD with a single neurochemical that affects how you are able to process memories and respond to them. I wonder if in the article it distinguished between people who lacked BDNF initially, or if it is something that it stimulated by the onset of PTSD (a particularly traumatic event). The former would indicate that certain people are predisposed to developing PTSD, while the latter would show that it is largely environmental and situational.

I think that is a very interesting point to make, Sarah. The article only focused on understanding the pathophysiology of PTSD in neural pathways and found the disease behavior to be partially attributed to a gene associated with BDNF. Understanding the genetics that underlie the disease, as you point out, is an important next step to examine whether BDNF mutation is a predisposing gene that is inherited or whether it is a mutation that arises from environmental factors. My hypothesis is that there are certainly other genes implicated in the pathology of PTSD as a result of both genetic and environmental factors.